Half-Life and Steady-State Dosing Principles

Half-life (t½) is the time required for the plasma concentration of a drug to decrease by 50%. It is determined by the drug's volume of distribution (Vd) and clearance (CL) via the formula t½ = 0.693 × Vd/CL. Steady state is achieved when the rate of drug administration equals the rate of elimination, occurring after approximately 4-5 half-lives of continuous dosing. At steady state, plasma drug concentrations fluctuate predictably between peak (Cmax) and trough (Cmin) levels within each dosing interval. Loading doses are used to achieve therapeutic levels rapidly when the half-life is long (e.g., digoxin t½ ~36 hours, amiodarone t½ ~40-55 days) by calculating: Loading Dose = Target Concentration × Vd. First-order elimination (most drugs) means a constant fraction of the drug is eliminated per unit time, while zero-order elimination (ethanol, phenytoin at high levels, aspirin overdose) eliminates a constant amount per unit time regardless of concentration — zero-order kinetics are clinically dangerous because small dose increases can produce disproportionately large increases in serum levels. Narrow therapeutic index (NTI) drugs require therapeutic drug monitoring (TDM) because the toxic concentration...